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Low weight may contribute to risk for natalizumab-induced PML



SAN DIEGO – Thinner multiple sclerosis patients may be at higher risk for natalizumab-induced progressive multifocal leukoencephalopathy, according to researchers from the Rocky Mountain Multiple Sclerosis Research Group in Salt Lake City.

The risk may derive from the drug’s higher mean plasma concentrations and the greater saturation of lymphocyte receptors in such patients, lead investigator Dr. John Foley suggested.

He and his team reviewed 38 natalizumab (Tysabri)-induced progressive multifocal leukoencephalopathy (PML) cases – 11.5% of the current global total – and found that 24 of the patients were 70 kg or less and 29 were 80 kg or less. The median weight of the PML patients was 64 kg, substantially lower than the weight of the average MS patient, at least at the Rocky Mountain clinic.

At 60 kg or less, "there is a striking elevation in PML cases. [The] incidence definitely trends towards patients with lower body weights," said Dr. Foley, founder of the clinic.

To further explore the issue, his team also analyzed clinical data from 301 of its own natalizumab patients, plus data from 826 patients in the Swedish Natalizumab Registry, 799 patients from phase III trials, and patients from other sources.

In doing so, they also found that patients weighing less than 75 kg tend to develop higher plasma concentrations of the monoclonal antibody over time and are more likely to saturate 95% or more of the lymphocyte receptors that natalizumab targets, exceeding the saturation goal of about 85%.

Patients who weighed no more than 70 kg had mean plasma concentrations of about 45 mcg/mL, whereas those over 150 kg had a mean level of less than 10 mcg/mL. Meanwhile, saturations appeared to escalate with concentration per patient-kilogram in a linear fashion from a mean of 85%-95%. "When you look at 95%-plus saturators, you see stratification into this real high-concentration and low-weight group," Dr. Foley said at the annual meeting of the American Academy of Neurology.

The findings led him to theorize that thinner patients are more at risk for PML because the higher saturations they develop block not only myelin-destroying lymphocytes from entering the central nervous system, as intended, but also lymphocytes that fight the JC virus, the cause of PML in those who carry it.

"We think there’s a link between serum concentration and saturation of lymphocytes in general, and that excessive saturation leads to near-complete stoppage of [lymphocyte] trafficking from blood vessels into brain parenchyma." Perhaps "we reach a threshold where we not only impede the cells that are programmed to cause MS, but also the trafficking of the cells that are programmed to kill viruses. We need to figure out what the optimal balance is," he said in an interview.

For now, "how we are approaching this is [by] dose-extending high-risk, JC virus antibody–positive populations out to 5-6 weeks, instead of dosing every 4 weeks," as the natalizumab label indicates. It "reduces concentrations in the last few weeks, and saturations decline. It may well be a viable approach for PML risk reduction," Dr. Foley said.

At the Rocky Mountain clinic, 14 patients who took natalizumab every 6 weeks had mean concentrations of 18.7 mcg/mL and saturations of 83.5%, whereas a group of about 160 patients on a 4-week dosing schedule had mean concentrations of 33.6 mcg/mL and saturations of 89.3%.

"You really want to avoid these high-concentration, high-saturation environments," he said.

The work was funded by the maker of natalizumab, Biogen Idec, and its distributor, Elan Pharmaceuticals. Dr. Foley is a scientific adviser to and a speaker for Biogen.

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